1. Field of the Invention
The present invention relates generally to the fields of pharmacology, neurology and psychiatry and to methods of treating depression. More specifically, this invention provides methods for the use of certain carbamate compounds for adjunctive use in the treatment of Major Depression and related depressive disorders.
2. Description of Related Art
Major depression and depressive disorders are common illnesses that affect more than 18.8 million Americans. (See, “Depression,” National Institute of Mental Health, Publication No. 00-3561 (2000)). There are several different kinds of depressive disorder Three of the more common depressive disorders include major depression, dysthymia, and bipolar disorder. Major depression is manifested by a combination of symptoms that interfere with a person's ability to function normally, including the ability to work, study, or sleep. Such disabling episodes of depression may occur only once but more commonly occur several times in a person's lifetime. Dysthymia, a less severe type of depression, involves long term chronic symptoms that do not disable a person but keep a patient from functioning well or feeling good. Bipolar disorder is a related mood disorder that is characterized by cycling mood changes from depression to manic.
Significant numbers of patients treated for depressive disorders do not respond to therapies presently available (i.e., electroconvulsive therapy (ECT), psychotherapy, and orally delivered antidepressant medications, or various combinations of all three therapies). Specifically, many patients do not respond to a single treatment modality such as a single antidepressant medication. This shortcoming exists despite the introduction of a variety of new more specific and significantly safer medications to the market place (e.g., Prozac®, Zoloft®, Paxil®). Approximately 20-30% of patients treated for depression with antidepressant medications fall into the category of being treatment-resistant and do not respond to the use of one of these agents. Janicak, P. G. and Martis, B. (1998), “Strategies for Treatment-Resistant Depression,” Clinical Cornerstone 1:58-71; Shelton, R. C. (1999), “Treatment Options for Refractory Depression,” J Clin. Psychiatry 60:57-63; Joffe, R. T. (1997), “Refractory Depression: Treatment Strategies, with Particular Reference to the Thyroid Axis,” J. Psychiatry Neurosci. 22:327-331.
Moreover, 30% to 50% of patients do not respond to their initial medication regardless of which class of drug is chosen. The treatment-resistant population consists of patients who have been treated unsuccessfully with multiple drug trials using different classes of orally administered antidepressants, psychotherapy, and potentially ECT.
A method of treatment for patients who have failed to respond to several classes of therapeutics used alone is ECT. Unfortunately, ECT by itself, also has a failure rate of approximately 30-40%. Walter, G., Rey, J. M., and Mitchell, P. B. (1999), “Practitioner Review: Electroconvulsive Therapy in Adolescents,” J Child Psychiatr 40: 325-334. ECT is a therapy that has been steadily increasing in use despite the stigma associated with its historical misuse in psychiatric medicine. ECT is now generally accepted by the American Psychiatric Association and the National Institute of Mental Health as being a safe and effective therapy for major depression. The side effects associated with ECT are generally mild and include headache, myalgia, nausea, memory problems, and confusion. Walter, G., Rey, J. M., and Mitchell, P. B. (1999), “Practitioner Review: Electroconvulsive Therapy in Adolescents,” J Child Psychiatr 40: 325-334.
Unfortunately, a small percentage of the ECT-treated patients experience significant cognitive impairments (pre- and/or post treatment memory deficits of durations of weeks to months), manic switching, and tachycardia such that treatment most be discontinued. In addition, ECT requires general anesthesia and a typical course of 8-12 treatments (each treatment takes approximately 15 minutes) administered bi- or tri-weekly. Perhaps the most discouraging aspect of ECT is that greater than half of the successfully treated ECT patients will relapse into clinical depression in less than a year. Sackeim, H. A., Prudic, J., Devanand, D. P., Decina, P., and Malitz, S. (1990), “The Impact of Medication Resistance and Continuation Pharmacotherapy on Relapse Following Response to Electroconvulsive Therapy in Major Depression,” J Clin Psychopharmacol 10: 96-104.
Nefazodone, a newer AD, inhibits both 5-HT 2 and 5-HT3 receptors. These antidepressive mechanisms suggest that activation of 5-HT2 and 5-HT3 receptors are not involved in the same biochemical pathways associated with selective serotonin reuptake inhibitor (SSRI)-induced efficacy. The antidepressive effects of SSRIs appears to involve 5-HT1 receptors (1A, 1B, and 1D); insomnia and sexual dysfunction effects have been attributed to 5-HT2 receptor activation and GI side effects have been attributed to 5-HT 3 receptor activation. Thase, M. E., Frazer, A., Gorman, J. M., Hirschfeld, R. M. and Roose, S. P., (2000), “Pharmacotherapy of Depression: New Strategies,” A Symposium of the American Psychiatric Association 2000 Annual Meeting.
The majority of antidepressants presently used are designed to affect one or both of the two major neurotransmitter systems of the brain, norepinephrine and serotonin. Antidepressants inhibit the neuronal reuptake (tricyclic antidepressants—norepinephrine (NE) and 5-HT, SSRIs—just 5-HT, selective norepinephrine reuptake inhibitors—just NE) or degradation (monoamine oxidase inhibitors) of one or both of these neurotransmitters. Although this is the common “first step” pharmacologic effect of antidepressants that leads to a corresponding increase in synaptic neurotransmitter concentrations, the precise biochemical pathways which lead to the ultimate therapeutic outcome have yet to be elucidated. It also is not appreciated why this pharmacologic first step occurs almost immediately after the medication is taken, whereas the patient does not experience relief from his/her symptoms of depression for weeks afterwards.
Recent theories proposed on the biochemical mechanisms of antidepressants (ADs) focus on adrenoceptors and the enzyme responsible for NE synthesis, tyrosine hydroxylase. Leonard, B. E., (1997), “Noradrenaline in Basic Models of Depression,” Eur Neuropsychopharmacol 7: 511-516. Many ADs produce a decrease in function and/or adrenoceptor density as well as decreases in the tyrosine hydroxylase levels in the brain. Thase, M. E., Frazer, A., Gorman, J. M., Hirschfeld, R. M. and Roose, S. P., (2000), “Pharmacotherapy of Depression: New Strategies,” A Symposium of the American Psychiatric Association 2000 Annual Meeting.
Thus the traditional ADs are limited by the endogenous pool of NE available in the vesicles of the nerve terminals. Those skilled in the art will realize that in pharmacology drugs that exert their effects indirectly (i.e., are dependent on the causing the release of or inhibiting the degradation of a primary endogenous molecule) are usually limited in the maximum effect they can produce. This efficacy limitation is a direct result of the limited pool of endogenous agonist. It is also conceivable that the lack of an adequate clinical response to oral reuptake inhibitors in select patient populations is a result of depleted or inaccessible pools of NE within the terminals of the presynaptic neurons. It is reasonable to assume that only with an intact endogenous supply of presynaptic NE can the initial pharmacologic impact of reuptake inhibition be expected to occur. Since this supply must be limited it is likely that in most cases the use of two or more medications or treatment that do not act on the same neurotransmitter system could be expected to have at least additive and very possibly synergistic effects. This positive therapeutic effect would not be expected to be as limited by the availability of one neurotransmitter because it would rely on multiple pathways and neurotransmitters
Thus there is a need to discover compounds having independent antidepressant action but that have atypical mechanisms of action. These compounds could be used in combination with conventional antidepressants that effect serotonin and norepinephrine receptors or neurotransmission and provide enhanced efficacy.